Oral pharmaceutical delivery system with improved sustained release

ABSTRACT

A solid orally ingested delivery system having at least one lipid, dry particles including at least one pharmaceutical, and at least one filler, where the dry particles are continuously coated by the lipid and form a homogeneous suspension with the lipid, and at least part of the pharmaceutical is microencapsulated with a polymer that releases in the pH range of about 5.0 to 7.0.

CROSS REFERENCE TO RELATED PATENTS

The application is a continuation-in-part of pending U.S. patentapplication Ser. No. 10/348,372, filed Jan. 21, 2003, which is acontinuation-in-part of pending U.S. patent application Ser. No.09/656,297, issued as U.S. Pat. No. 6,541,025, filed Sep. 6, 2000, whichis a continuation-in-part of U.S. patent application Ser. No. 09/476,483issued as U.S. Pat. No. 6,340,471B1, filed Dec. 30, 1999, all of whichare hereby incorporated in their entirety by reference.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical delivery system thatincreases the sustained release properties of drugs. Said deliverysystem includes both human and veterinary applications. Morespecifically, the present invention relates to an orally ingestedpharmaceutical delivery system that is a solid lipid suspension thatprovides improved sustained release.

BACKGROUND OF THE INVENTION

Drug efficacy generally depends upon the ability of the drug to reachits target in sufficient quantity to maintain therapeutic levels for thedesired time period. Orally ingested drugs must overcome severalobstacles to reach their desired targets. Before orally ingested drugsenter the general circulation of the human body, they are absorbed intothe capillaries and veins of the upper gastrointestinal tract and aretransported by the portal vein to the liver. The pH and enzymaticactivities found in gastrointestinal fluids may inactivate the drug orcause the drug to dissolve poorly and not be absorbed. In addition,following their absorption in the intestine, orally ingested drugs areoften subject to a “first pass” clearance by the liver and excreted intobile or converted into pharmacologically inactive metabolites.

The oral ingestion of hormones, such as testosterone or estrogen, hasproven challenging. Testosterone is administered for oral ingestion in abonded form as testosterone undecanoate, methyltestosterone, ortestosterone cyclodextrin, to avoid the first pass effect. When it isadministered in a regiment of hormone replacement therapy, it is desiredto have sustained release properties, yet these forms of testosteronemust be taken multiple times daily.

Of particular interest is the delivery of testosterone in the unbondedform. The unbonded form of testosterone is more stable than its bondedpredecessors. More of the active ingredient is delivered in a smallerdosage. The unbonded form is a simpler and less expensive manufacturingprocess in that the additional step of bonding the testosterone iseliminated. Further, the unbonded testosterone is administered with orwithout food, unlike the bonded form which is administered with foodconsumption.

“Sustained Release” generally refers to release of a drug whereby thedrug concentration in the serum of the patient is maintained at thedesired level over a period of time. The longer the drug is at thedesired level, the better the sustained release properties are. It isdesirable to have the desired level be maintained for 12 h or more, sothat only one to two doses of a drug need to be taken daily. A secondindicator of sustained release properties is the t_(max) of the drug,which is the time after administration of the drug that the serumconcentration reaches its maximum level. A larger t_(max) may indicate aslower and more sustained release of the drug into the blood. A varietyof methods and formulations are used to provide sustained release ofdrugs. Some of the methods are disclosed in U.S. Pat. No. 5,567,439,which is hereby incorporated by reference, which discloses controlledrelease systems using a shearform matrix.

The use of a lipid-based solid oral delivery system with improved tastemasking is disclosed in U.S. Pat. No. 6,340,471B1. U.S. Pat. No.5,229,131 discloses a sustained release system that uses one or moreindividual drug-containing subunits in a unitary drug depot, such as atablet or capsule.

The use of coatings on pharmaceuticals to provide sustained releaseproperties, taste and odor masking, and delayed release are known in theart. One line of products commercially available for the coating ofpharmaceuticals is EUDRAGIT® polymers marketed by Pharma Polymers.Polymer coatings are prepared that release at the desired pH to deliverdrugs to targeted portions of the gastrointestinal system.

None of the above-referenced patents describe the present invention asdisclosed and claimed herein.

SUMMARY OF THE INVENTION

The present invention comprises a solid orally ingested delivery systemcomprising at least one lipid, dry particles including at least onepharmaceutical, and at least one filler, wherein the dry particles arecontinuously coated by the lipid and form a homogeneous suspension withthe lipid. At least part of the pharmaceutical is microencapsulated witha polymer that releases in the pH range of from about 5.0 to 7.0. Thesuspension, when melted, exhibits thixotropic and/or pseudoplasticproperties. The suspension is formed into the desired dose by molding orpouring the suspension when in a liquid or semi-liquid state. Theprocess for preparing the present delivery system comprises melting thelipid, blending the dry particles which include the pharmaceutical, atleast one filler and, optionally, flavorings with the melted lipid, andpouring or molding the suspension to provide the solid dose. Thesuspension, when melted, exhibits thixotropic and pseudoplastic flowproperties.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph demonstrating the serum concentration of various dosesof testosterone over time when administered in a lipid formulation todogs by oral ingestion.

FIG. 2 is a graph demonstrating the serum concentration of various dosesof testosterone over time when administered in a micronized formulationto dogs by oral ingestion.

FIG. 3 is a graph demonstrating the serum concentration of 250 mg doseof testosterone with various amounts of rupturing agent over time whenadministered in a lipid formulation to dogs by oral ingestion.

FIG. 4 is a graph demonstrating the serum concentration of 250 mg doseof testosterone with various types of surfactant over time whenadministered in a lipid formulation to dogs by oral ingestion.

FIG. 5 is a graph demonstrating the serum concentration of 250 mg doseof testosterone with 100 mg microencapsulated with various coatings and250 mg micronized, over time when administered in a lipid formulation todogs by oral ingestion.

DETAILED DESCRIPTION OF THE INVENTION

The lipids of the present invention may be of animal, vegetable ormineral origin, which are substantially water-insoluble, inert,non-toxic hydrocarbon fats and oils and derivatives thereof, and maycomprise any of the commonly commercially available fats or oilsapproved by the Food & Drug Administration, having melting points in therange of about 90 to 160° F. (32 to 71° C.). The lipid may comprise avegetable oil base commonly known as hard butter. Hard butters arehydrogenated, press fractionated, or other processed oils that areprocessed or recombined to have a solid fat index (percent solid fat vs.temperature) similar to that of cocoa butter. However, other lipids maybe used that are relatively hard or solid at room temperature, but meltrapidly in the mouth at a temperature of about 92° to 98° F. (29 to 32°C., mouth temperature). The lipid is employed in the amounts within therange of from about 20 to 50%. Above about 50%, the suspension flows tooreadily and does not exhibit thixotropic or pseudoplastic flowproperties. When present below about 20%, the amount of lipid is notsufficient to completely coat the dry particles.

It is expected that the lipid formulation would have improved sustainedrelease properties over that of granulated pharmaceuticals alone, sincethe lipids may hinder the solubilizing of the pharmaceutical in thegastrointestinal tract and retard absorption.

Examples of suitable lipids include tallow, hydrogenated tallow,hydrogenated vegetable oil, almond oil, coconut oil, corn oil,cottonseed oil, light liquid petrolatum, heavy liquid petrolatum, olein,olive oil, palm oil, peanut oil, persic oil, sesame oil, soybean oil orsafflower oil. Additionally, stearines can be used as a lipid in thepresent invention. The addition of stearines to the product provides thefavorable property of mold-release. Further, the addition of stearinesraises the melting point of the composition as high as about 100° F.(38° C.), which is particularly beneficial when the product is shippedor stored in unrefrigerated compartments.

The fillers of the present invention are pharmacologically inert andoptionally nutritionally beneficial to humans and animals. Such fillersinclude cellulose such as microcrystalline cellulose, grain starchessuch as cornstarch, tapioca, dextrin, sugars and sugar alcohols such assucrose sorbitol, xylitol, mannitol and the like. Preferred fillersinclude non-fat milk powder, whey, grain brans such as oat bran, andfruit and vegetable pulps. Preferred fillers are finely divided and havea preferred average particle size in the range of about 0.10 to 500microns. More preferred fillers are from about 50 to 500 microns.Particles less than about 50 microns tend to cause difficulty incontrolling dust when handling. The fillers are present in the drugdelivery device in a concentration of about 50 to 80%. Optionally, thepharmaceutical particles can also serve as filler in the deliverysystem.

Optionally, the filler may include an emulsifier or surfactant. Anyemulsifier or surfactant approved for use in foods by the Food and DrugAdministration and having a relatively low HLB value, in the range ofabout 1 to 3, is suitable for use in the present invention. Theappropriate surfactant minimizes the surface tension of the lipid,allowing it to oil wet and encapsulate the non-oil solid particles.Typically, the surfactant is present in the delivery system in theconcentration of about 0.1 to 1.0%. Suitable surfactants include alkylaryl sulfonate, alkyl sulfonates, sulfonated amides or amines, sulfatedor sulfonated esters or ethers, alkyl sulfonates, of dioctylsulfonosuccinate and the like, a hydrated aluminum silicate such asbentonite or kaolin, triglycerol monostearate, triglycerolmonoshortening, monodiglyceride propylene glycol, octaglycerolmonooleate, octaglyceron monostearate, and decaglycerol decaoleate. Thepreferred surfactant is lecithin.

At least part of the pharmaceutical is microencapsulated. Any knownmethod of encapsulation is suitable in the present invention. Apreferred method involves slowly blending the drug with a filming agentsolution to form granulated particles. The granulated particles areallowed to dry on a tray and are sieved to the desired size, typicallyin the range of from about 200 to 500 microns. In a preferredembodiment, the pharmaceutical is a mixture of encapsulated andnon-encapsulated pharmaceutical. The mixture of encapsulated tonon-encapsulated can be in the range of about 1:10 to 10:1. Morepreferably, the mixture is in the range of 2:3 to 3:2 encapsulated tonon-encapsulated.

The three types of methylcellulose tested were: (1) EUDRAGIT L100-55,designed to release in the duodenum with a pH in the range of 5.5 to6.0, (2) EUDRAGIT L 100, designed to release in the jejunum at a pH ofabout 6.0 to 7.0, and (3) EUDRAGIT S 100, designed to release in theileum at a pH of >6.5. Since the ingested pharmaceutical would proceeddown the digestive tract in the order of (1) duodenum, (2) jejunum and(3) ileum, it was expected that the t_(max) for each composition wouldincrease as the pH range would increase, thereby providing improvedsustained release properties. Therefore, the t_(max) would increase inthe order of the EUDRAGIT L100-55 to the EUDRAGIT L100 to EUDRAGIT S100. Further, the t_(max) of each microencapsuled composition wasexpected to exceed that of the non-microencapsulated composition.Surprisingly, it was discovered that the EUDRAGIT L100-55 gave thegreatest t_(max) of 12 h, and demonstrated the best sustained releaseproperties, with a serum concentration in the desired range for at least12 h. The EUDRAGIT S 100 gave the poorest sustained release propertieswith a t_(max) of 9 and 6 h of serum concentration in the desired range.The EUDRAGIT L 100 gave an acceptable t_(max) of 9 h with 12 h of serumconcentration in the desired range.

The preferred pH values for controlled release are in the range of pH4.0 to 7.0, more preferably, 5.5 to 7.0. One line of productscommercially available for the coating of pharmaceuticals is EUDRAGIT®polymers marketed by Pharma Polymers. Polymer coatings are prepared thatrelease at the desired pH to deliver drugs to targeted portions of thegastrointestinal system. Of particular interest are EUDRAGIT® L100 andEUDRAGIT® L 100-55. These polymers release at a pH in the range of about5.5 to 7.0, and have been found to be surprisingly superior to similarpolymers that release at greater than pH 6.5 (EUDRAGIT® S100).

Typically the pharmaceutical is present in the delivery device in aconcentration of 30% or less. However, the pharmaceutical can compriseall of the dried particles, acting as a filler, to provide the necessarydose.

The pharmaceuticals contemplated in the present invention areadministered by oral ingestion. The pharmaceuticals include drugs thathave reduced bioavailability when administered orally, and drugs that donot have reduced bioavailability. Drugs that have reducedbioavailability include drugs such as analgesics, anti-inflammatoryagents, gastrointestinal medications, hormone products, cardiovascularpreparations, anticoagulants and antibiotics. Specific drugs includeinsulin, heparin, oligosaccharides, aspirin, testosterone andprednisolone. Pharmaceuticals further includes vitamins and minerals.Pharmaceuticals also includes synthetic and natural food supplements,such as glucosamine, chondroitin, bee pollen, St. John's wort,echninaecia, etc. Additional pharmaceuticals are contemplated for thepresent invention, and are disclosed in U.S. Pat. No. 4,880,634, andU.S. Pat. No. 5,965,164, which are hereby incorporated by reference.

Optionally, the dry particles include flavorings that make the devicetaste and smell appealing to humans or animals. The flavorings can benatural or synthetic, and can include fruit, citrus, meat, chocolate,vanilla, fish, butter, milk, cream, egg or cheese flavorings. Theflavorings are typically present in the device in the range of about0.05 to 50.0%.

The delivery device may also include other pharmaceutically acceptableagents, such as sweetening agents, including hydrogenated starchhydrolysates, synthetic sweeteners such as sorbitol, xylitol, saccharinsalts, L-aspartyl-L-phenylalanine methyl ester, as well as coloringagents, other binding agents, lubricants, such as calcium stearate,stearic acid, magnesium stearate, antioxidants such as butylated hydroxytoluene, antiflatuants such as simethicone and the like.

Optionally, rupturing agents are used to rapidly deliver thepharmaceutical into the recipient's system. A typical rupturing agent isa starch that swells in the presence of water. Various modifiedstarches, such as carboxymethyl starch, currently marketed under thetrade name EXPLOTAB or PRIMOGEL are used as rupturing agents. Apreferred rupturing agent is sodium starch glycolate. When ingested, thecapsule or pellet swells in the presence of gastric juices and ruptures.Preferably, the rupturing agent is present in the delivery system fromabout 1 to 5%.

In one embodiment of the present invention, the rupturing agent ispresent inside the microcapsule. As water penetrates the microcapsule,it swells the starch and ruptures the capsule, rapidly delivering thepharmaceutical to the system. Additional rupturing agents are disclosedin U.S. Pat. No. 5,567,439, which is hereby incorporated by reference.

In another embodiment, the rupturing agent is present in the lipidsuspension, which ruptures the pellet, but leaves the microcapsulesintact. This allows the delayed delivery of the drug farther along inthe digestive system, or in the intestines. The present invention isparticularly effective in this embodiment, in that the ingested pelletmay be chewable, where the pellet cleaves in the lipid suspension whenchewed, but leaves the microcapsules intact. Tablets or gel capsules,when chewed, typically result in damage to or rupturing of themicrocapsules defeating the effectiveness of the microcapsules.

The process for preparing the above delivery system comprises meltingthe lipid and mixing with the surfactant. The dry particles are mixedwith the melted lipid mixture to form a suspension exhibitingpseudoplastic and/or thixotropic flow properties, and poured or moldedto provide solid dosage forms.

The dry particles, which include the pharmaceutical, filler and optionalflavorings and additives, are pre-blended and typically have a particlesize in the range of from about 50 to 150 microns. The pre-blendedparticles are gradually added to the heated lipid base until a highsolid suspension is obtained, typically in the range of about 50 to 80%particles and from about 50 to 20% lipid.

Slow addition of the dry particles is critical in the production of thedevice, to insure that the particles are suspended in their micronizedstate and not as agglomerated clumps. Moreover, rapid addition can causethe mixing process to fail in that the melted suspension will not havethe desired flow properties, but instead will be a granular oily mass (asign of product failure). The mixing step is accomplished in a heatedmixing device that insures thorough mixing of all materials with minimalshear, such as a planetary mixer or a scrape surface mixer. After thesuspension is formed, the product is poured into molds and allowed tocool. De-molding and packaging are then performed. Alternatively, thesuspension can be super-cooled and sheeted in a semi-soft format. Thesheet is processed through forming rolls containing a design orconfiguration that embosses and forms the final shape.

The following examples are to illustrate the claimed invention and arenot intended to limit the claims in any way. All of the percentages areby weight unless otherwise indicated.

EXAMPLES

Example I was prepared according to the following procedure. This datawas taken to determine the dosage range needed to achieve the desiredblood serum level above about 300 ng/dl for 12 h or more. Additionally,the t_(max) was determined as another indicator for sustained release,i.e., increasing t_(max) indicates increased delivery time for thepharmaceutical, or increased sustained release properties.

Forming the Suspension

The lipid (hydrogenated vegetable oil sold under the trademark KLX®) washeated in a HOBART 5 Quart planetary mixer jacketed with a heatingmantle in the range of about 140 to 150° F. (60 to 66° C.) and melted.The surfactant, lecithin, was added to the lipid with mixing, and themixture was allowed to cool to about 135° F. (° C.).

The dry particles, including the pharmaceutical (micronized, i.e., 3 to5 microns, testosterone), the rupturing agent (sodium starch glycolate,sold under the trademark EXPLOTAB), and fillers (microcrystallinecellulose, sold under the trademark EUDRAGIT S100, dry milk, salt andpowdered sugar) were screened to a particle size in the range of about200 and 500 microns and dry-blended. The dry particles were slowly addedincrementally to the lipid/surfactant mixture with mixing over a periodof about 1 hour, to provide a smooth suspension with no lumps oragglomerations. The suspension exhibited thixotropic and pseudoplasticflow properties. It was molded and cooled to about 70° F. (21° C.). Thesuspension shrank as it cooled, and easily released from the mold wheninverted.

Forming A Suspension of Testosterone in a 250 mg Dose

TABLE 1 BATCH FORMULA Ingredient Weight (grams) % KLX (lipid) 36.10038.00 EXPLOTAB (rupturing agent) 4.750 5.00 EUDRAGIT S100 (cellulose)4.750 5.00 Dry milk, low heat (filler) 9.500 10.00 Powdered sugar(filler) 14.250 15.00 Lecithin (surfactant) 0.950 1.00 Salt 0.190 0.20Testosterone 24.938 26.25 Totals 95 100.45

Example 1 Varying the Testosterone Dose 25, 50, 100, 250 mg

In vivo Evaluation

A study using six dogs (female beagles) was made to obtain preliminarypharmacokinetic data following a single oral dose of the deliverysystem. The dogs were 13-24 months old, and weighed in the range of 10.4to 13.2 kg.

The dosing was done in four sequential one day intervals with a minimumtwo day rest period in between each interval. Blood was drawnimmediately before the dose was administered. The results revealedminimal levels of testosterone. The animals were given the placebo ortest article, as described above, at approximately the same time eachday, immediately prior to being fed. The dog ate its food within 30minutes of the dose being administered.

Blood samples were collected pre-dose and at 0.5, 1, 2, 4, 5, 6, 8 and24 hours post dosing. At each time point, a minimum of 3 mL whole blood(or minimum volume determined by assay requirement) were collected byvenipuncture of the jugular vein into non-heparinized Vacutainer tubes.The blood was centrifuged to obtain serum, which was kept on ice untilplaced into an appropriately sized vial, and frozen at −70° C. Thesamples remained frozen until delivered on dry ice to the lab foranalysis. The lab used radioimmunoassay to analyse for testosterone.

Example 1 Results

Average Serum Testosterone (ng/dl)

TABLE 2 Testosterone Dose (mg) 25 50 100 250 Testosterone TestosteroneTestosterone Testosterone Time (h) (ng/dl) (ng/dl) (ng/dl) (ng/dl) 0 0 10 26   0.5 286 154 270 264 1 390 286 309 555 2 425 376 450 835 4 118 288522 1032 5 35 215 618 829 6 53 107 357 980 8 23 54 422 757 24  1 7 2 8t_(max) 2 h 2 h 5 h 4 h

The data from Table 2 is plotted in FIG. 1, Graph 1. The t_(max) (timeto maximum concentration) increased with increasing dosage up to the 100mg dosage, where it plateaued out.

Control 1 Varying the Testosterone Dose 25, 50, 100, 250 mg in a GelCapsule

Samples of micronized testosterone, not in a lipid suspension, wasplaced in a gelatin capsule and administered to dogs as described inExample 1. This test was run to compare the sustained release propertiesof a lipid suspension to those of a micronized pharmaceutical. Theresults are summarized in Table 3.

Control 1 Results

Average Serum Testosterone (ng/dl)

TABLE 3 Testosterone Dose (mg) 25 50 100 250 Testosterone TestosteroneTestosterone Testosterone Time (h) (ng/dl) (ng/dl) (ng/dl) (ng/dl) 0 490 0 7   0.5 253 150 772 1315 1 664 204 916 1306 2 238 324 703 1786 4 123266 372 1009 5 109 293 332 775 6 57 295 278 542 8 20 165 143 412 24  1 32 16 t_(max) 1 h 2 h 1 h 2 h

The results of Table 3 are plotted in FIG. 2, Graph 2. The t_(max) forthe samples ranged from 1 to 2. Increasing the dosage level did notincrease the t_(max) as it did for the lipid suspension of Example 1.Table 4 provides the sustained release properties of Example 1 andControl 1 by comparing t_(max) for each sample.

Time to Maximum Concentration (t_(max)) Example 1and Control 1

TABLE 4 Testosterone Dose Example 1, Control 1, (mg) lipid t_(max) (h)granulated t_(max) (h) 25 2 1 50 2 2 100 5 1 250 4 2

The lipid suspension (Example 1) provides improved sustained releaseproperties at doses of 100 mg and 250 mg, as indicated by increasedt_(max) when compared to Control 1, the granulated testosterone. Smallerdoses fail to display increased t_(max). It is important to note thatthe present data is taken using dogs as test animals. It is generallyrecognized that the metabolism of dogs is higher than that of humans,and that humans will typically display higher blood serum levels for agreater period of time under similar test conditions. It is expectedthat humans will experience even greater sustained release levels thanthose shown in the dogs.

Although the lipid formulation provided improved sustained releaseproperties when compared to the micronized testosterone, thetestosterone was delivered in a sharp spike at 4 h, which then taperedoff.

Example 2

Varying the Amount of Rupturing Agent

This study was made to determine the effect of the amount of rupturingagent on sustained release properties. Samples of a lipid suspensionwere prepared as in Example 1, wherein the amount of testosteroneadministered was 250 mg, and the amount of rupturing agent was varied asfollows: 0, 1, 2 and 5%.

In vivo Evaluation

A study using four dogs (female beagles) was made to obtain preliminarypharmacokinetic data following a single oral dose of the deliverysystem. The dogs were 13-24 months old, and weighed in the range of 11.1to 12.6 kg.

The dosing was done in four sequential one day intervals with a minimumfour day rest period in between each interval. Blood was drawnimmediately before the dose was administered. The results revealedminimal levels of testosterone. The animals were given the placebo ortest article, as described above, at approximately the same time eachday, immediately prior to being fed. The dog ate its food within 30minutes of the dose being administered.

Blood samples were collected pre-dose and at 3, 6, 8, 10, 12, 16, 20 and24 hours post dosing. At each time point, a minimum of 3 mL whole blood(or minimum volume determined by assay requirement) were collected byvenipuncture of the jugular vein into non-heparinized Vacutainer tubes.The blood was centrifuged to obtain serum, which was kept on ice untilplaced into an appropriately sized vial, and frozen at −70° C. Thesamples remained frozen until delivered on dry ice to the lab foranalysis. The lab used radioimmunoassay to analyse for testosterone.

Test Results

Average Serum Testosterone (ng/dl)

TABLE 5 % EXPLOTAB* Time (h) 5 0 1 2  0 2.0 0.0 2.5 0.3  3 433.5 485.8274.0 690.8  6 1257.0 537.3 561.3 920.0  8 479.8 520.8 772.5 776.0 10330.3 410.5 553.3 840.0 12 224.5 243.5 449.3 293.8 16 31.5 213.0 212.861.3 20 12.0 72.3 88.0 29.0 24 6.8 48.3 54.5 27.3 tmax 6 6 8 6*The rupturing agent.

The results shown in Table 5 are plotted in FIG. 3, Graph 3. Graph 3indicates that 5% EXPLOTAB releases more testosterone at once withC_(max) (maximum concentration) of 1257 ng/dl. However, varying therupturing agent concentration did not increase the t_(max), except atthe concentration level of 1%.

Example 3 Varying the Surfactant

An in vivo evaluation, of the present invention was made, using theformulation from Table 1, but varying the surfactant as follows todetermine the impact of varying the surfactant on sustained releaseproperties. The same procedure was followed as described in Example 3,except that three dogs were used and there was a two day washout.

Average Serum Testosterone (ng/dl)

TABLE 6 Surfactant Time (h) Lecithin No Surfactant DUREM 300* 0   1.10.0 0.0 0.5 51.3 94.3 104.7 1.0 397.7 277.3 217.7 2.0 929.3 609.7 1136.74.0 1558.0 1410.0 581.0 5.0 1561.3 702.3 591.0 6.0 1039.3 632.7 688.78.0 502.0 375.0 576.3 24.0  10.0 48.0 59.3 tmax 5 h 4 h 2 h*Monodiglyceride propylene glycol surfactant.

The results given in Table 6 are plotted in FIG. 4, Graph 4. The leastfavorable surfactant, in terms of t_(max) is DUREM 300, with a t_(max)of 2 h.

Example 4 100 mg Microencapsulated, 150 mg Micronized TestosteroneCombined for 250 mg Dose

The preferred composition, having a combination of 100 mgmicroencapsulated testosterone with 150 mg micronized testosterone wasprepared. The micronized testosterone was expected to give a quickrelease of testosterone in the stomach. The microencapsulatedtestosterone was expected to give delayed delivery of testosterone.Three samples were microencapsulated with three types of methylcellulosedesigned to release at different pH values. The fourth sample wasprepared with all micronized testosterone (250 mg).

The three types of methylcellulose tested were: (1) EUDRAGIT L100-55,designed to release in the duodenum with a pH in the range of 5.5 to6.0, (2) EUDRAGIT L 100, designed to release in the jejunum at a pH ofabout 6.0 to 7.0, and (3) EUDRAGIT S 100, designed to release in theileum at a pH of >6.5. Since the ingested pharmaceutical would proceeddown the digestive tract in the order of (1) duodenum, (2) jejunum and(3) ileum, it was expected that the t_(max) for each composition wouldincrease as the pH range would increase. Therefore, the t_(max) wouldincrease from the EUDRAGIT L100-55 having the lowest t_(max), then tothe EUDRAGIT L100 to the EUDRAGIT S 100 having the highest t_(max).Further, the t_(max) of each microencapsuled composition was expected toexceed that of the non-microencapsulated composition.

The four samples were formulated into a lipid suspension as disclosed inExample 1 and given to four dogs. Serum levels of testosterone weremeasured as in Example 1. TABLE 7 Serum Levels of Testosterone (ng/dl)pH 5.5-6.0 pH 6.0-7.0 pH > 6.5 Release, Release, Release, Time (h)Un-encapsulated L100-55 L100 S 100  0 79 5 12 15   1.5 438 166 314 254 3 649 179 333 290  6 603 426 487 271  9 302 438 599 348 12 147 576 377344 15 52 351 266 195 18 25 86 90 173 21 18 55 75 190 24 16 30 112 117tmax 3 12 9 9

The date of Table 7 is plotted in FIG. 5, Graph 5. A clear increase insustained release is indicated with the increase in the t_(max).Surprisingly, the greatest increase is not in the >6.5 pH, as expected,but in the 5.5-6.0 pH cellulose coating (EUDRAGIT L 100-55), which gavea four fold increase of unencapsulated testosterone, and a 33% increaseover that of EUDRAGIT L100 or EUDRAGIT S 100. When the delivery time forserum concentration above 300 ng/dl is taken into account, both EUDRAGITL100-55 and EUDRAGIT L 100 show sustained release properties of at least12 h. The EUDRAGIT S 100 showed unacceptable sustained release time of 6h of serum concentration above 300 ng/dl.

1. A sustained release solid orally ingested delivery system comprisingat least one lipid and dry particles having a particle size greater thanabout 50 microns, wherein the dry particles contain at least onepharmaceutical, wherein the dry particles are continuously coated withthe lipid and form a homogeneous suspension with the lipid; wherein thesuspension, when melted exhibits pseudoplastic and/or thixotropicproperties; wherein at least part of the pharmaceutical is encapsulatedwith a polymer that dissolves at a pH in the range of from about 4.0 toabout 7.0, and the ratio of unencapsulated to encapsulatedpharmaceutical is in the range of about 1:10 to 10:1; and wherein thesuspension is formed or shaped into the appropriate solid dosage form bymolding or pouring the suspension when in a liquid or semi-liquid state.2. The delivery system of claim 1 wherein the system contains arupturing agent.
 3. The delivery system of claim 1 wherein the systemcontains a surfactant.
 4. The delivery system of claim 1 wherein ratioof unencapsulated to encapsulated is in the range of about 3:2 to 2:3.5. The delivery system of claim 1 wherein the polymer dissolves at a pHin the range of about 5.0 to 7.0.
 6. The delivery system of claim 1,wherein the pharmaceutical is selected from the group consisting ofanalgesics, antibodies, anti-inflammatory agents, cardiovascular drugs,gastrointestinal medicines, hormones and laxatives.
 7. A sustainedrelease solid orally ingested delivery system comprising at least onelipid and dry particles having a particle size greater than about 50microns, wherein the dry particles contain at least one pharmaceutical,a surfactant and a rupturing agent, wherein the dry particles arecontinuously coated with the lipid and form a homogeneous suspensionwith the lipid; wherein the suspension, when melted exhibitspseudoplastic and/or thixotropic properties; wherein at least part ofthe pharmaceutical is encapsulated with a polymer that dissolves at a pHin the range of from about 5.0 to about 7.0, and the ratio ofunencapsulated to encapsulated pharmaceutical is in the range of about2:3 to 3:2; and wherein the suspension is formed or shaped into theappropriate solid dosage form by molding or pouring the suspension whenin a liquid or semi-liquid state.
 8. The delivery system of claim 7,wherein the pharmaceutical is selected from the group consisting ofanalgesics, antibodies, anti-inflammatory agents, cardiovascular drugs,gastrointestinal medicines, hormones and laxatives.
 9. A method ofpreparing a sustained release solid orally ingested delivery systemcomprising melting at least one lipid, blending dry particles whichinclude at least one pharmaceutical and at least one filler to form asuspension, and pouring or molding the suspension to provide a solidoral delivery system; wherein the pharmaceutical is encapsulated andunencapsulated in a ratio of 1:10 to 10:1 encapsulated tounencapsulated; wherein the pharmaceutical is encapsulated with apolymer that dissolves at a pH in the range of from 4.0 to 7.0; andwherein the system, when melted, exhibits thixotropic and pseudoplasticflow properties.
 10. The method of claim 9, wherein the delivery systemincludes a rupturing agent.
 11. The method of claim 9, wherein the ratioof encapsulated to non-encapsulated is in the range of 2:3 to 3:2. 12.The method of claim 9, wherein the microencapsulating film releases at apH in the range of about 5.0 to 7.0.
 13. The method of claim 9, whereinthe microencapsulating film releases at a pH in the range of about 5.5to 7.0.
 14. The method of claim 9, wherein the delivery system includesa surfactant.
 15. A method of preparing a sustained release solid oraldelivery system comprising a) microencapsulating at least part of apharmaceutical, b) melting at least one lipid, c) dry-mixing dryparticles including the pharmaceutical, and at least one filler, d)mixing the dry particle mixture with the melted lipid to form asuspension, wherein the dry particles are continuously coated by thelipid and form a homogeneous suspension with the lipid; wherein at leastpart of the pharmaceutical is encapsulated with a polymer that dissolvesat a pH in the range of from about 4.0 to about 7.0, and the ratio ofunencapsulated to encapsulated pharmaceutical is in the range of about1:10 to 10:1; wherein the suspension, when melted, exhibits thixotropicand/or pseudoplastic properties, wherein the suspension is formed intothe desired dose by molding or pouring the suspension when in a liquidor semi-liquid state.
 16. The method of claim 15, wherein saidpharmaceutical is selected form the group consisting of analgesics,antibodies, anti-inflammatory agents, cardiovascular drugs,gastrointestinal medicines, hormones and laxatives.
 17. A method ofadministering a pharmaceutical to a human or animal comprisingadministering by oral ingestion to the human or animal a therapeuticamount of a delivery system comprising at least one lipid and dryparticles having a particle size greater than about 50 microns, whereinthe dry particles contain at least one pharmaceutical, wherein the dryparticles are continuously coated with the lipid and form a homogeneoussuspension with the lipid; wherein the suspension, when melted exhibitspseudoplastic and/or thixotropic properties; wherein at least part ofthe pharmaceutical is encapsulated with a polymer that dissolves at a pHin the range of from about 4.0 to about 7.0, and the ratio ofunencapsulated to encapsulated pharmaceutical is in the range of about1:10 to 10:1; and wherein the suspension is formed or shaped into theappropriate solid dosage form by molding or pouring the suspension whenin a liquid or semi-liquid state.
 18. The delivery system of claim 1wherein the pharmaceutical is testosterone.
 19. The method of claim 9,wherein the pharmaceutical is testosterone.
 20. The method of claim 17,wherein the pharmaceutical is testosterone.